The purpose of these experiments is to gain a better understanding of the mode of action of selected antitumor agents by conducting in vitro and in vivo studies with mouse tumor systems. L1210 leukemia and Lewis lung carcinoma were used to measure drug effects. In vitro studies, with hematoporphyrin and light cell damage on melphalan and actinomycin-D cytotoxicity, were concluded this year and indicated a synergistic response. Two feet-deoxy-5-azacytidine (DAC) and some analogues have been studied in vitro and in vivo with L1210. Biochemical modulation occurs with thymidine and immune modulation occurs with pyran copolymer. In vitro cytotoxicity studies with DAC indicate a maximum cell kill of 3 to 4 logs is achievable with optimal conditions of concentration andexpoure time. In vivo cytotoxicity studies with DAC indicate log cell kills of greater than 7 logs at optimal doses. Reasons for this discrepancy are being studied. Advanced L1210 tumor in mice, with late treatment, indicate drug resistant cells (deoxycytidine kinase poor mutants) may be a major problem with DAC. Collaterally sensitive drugs such as cytoxan, BCNU, dihydro-5-azacytidine, 3-deazauridine and tiazofurin are being considered as potential solutions to this drug resistant.